Organocatalyzed Michael Addition Reaction by Novel (2R,3aS,7aS)-Octa-hydroindole-2-carboxylic Acid, a New Fused Proline

Abstract

We present here the results obtained in our study on organocatalytic enantioselective Michael addition reaction of acetone to different nitroolefines using (2R,3aS,7aS)-octahydroindole-2-carboxylic acid [(R,S,S)-Oic] as a new and suitable catalyst for this process. Computational calculations support the results obtained with (R,S,S)-Oic versus its diastereomeric form (S,S,S)-Oic. The final products are obtained in good yields and moderate enantioselectivities (up to 58% ee).

Michael addition - nitroolefines - ketones - Oic - organocatalysis - enantioselectivity

References and Notes

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15

Typical Experimental Procedure To a suspension of catalyst (10 mol%) and nitroalkene (0.5 mmol) in DMF (4 mL), acetone (13.5 mmol, 1 mL) was added, and the resulting mixture was stirred at 25 ˚C for the time indicated in Table  [³] . After that time the reaction was quenched with sat. NH₄Cl (2 × 20 mL), the layers were separated and the aqueous layer extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (2 × 20 mL), dried (MgSO₄), filtered, and rotatory evaporated to give a residue which was purified by flash chromatography using hexane-EtOAc (7:3) as an eluent.
Selected Spectral Data
Compound 8j: Following the general procedure, compound 8j was obtained after 10 d at r.t. as a white solid in 68% yield; mp 135-136 ˚C. ^¹H NMR (400 MHz, CD₃OD): δ = 2.05 (s, 3 H), 2.88 (dd, J = 2.6, 7.2 Hz, 2 H), 3.82-3.89 (m, 1 H), 4.57 (dd, J = 9.2, 12.4 Hz, 1 H), 4.70 (dd, J = 6.3, 12.4 Hz, 1 H), 6.70-6.74 (m, 2 H), 7.06-7.10 (m, 2 H). ^¹³C NMR (100 MHz, CD₃OD): δ = 30.4, 40.0, 47.2, 80.9, 116.5, 129.8, 131.5, 157.9, 208.8. The ee of the product was determined by HPLC using a Daicel Chiralpak IA column (n-hexane-i-PrOH = 90:10, flow rate 1 mL/min, λ = 230 nm): t _R(major) = 29.1 min; t _R(minor) = 26.9 min. HRMS: m/z calcd for C₁₁H₁₃NNaO₄: 246.0737; found: 246.0728 [M⁺ + Na]. [α]_D ^²² 7.3 (c 1.0, MeOH, 33% ee).
Compound 8k: Following the general procedure, compound 8k was obtained after 10 d at r.t. as a yellow oil in 74% yield; mp 131-133 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 2.11 (s, 3 H), 2.88 (d, J = 7.1 Hz, 2 H), 3.96 (q, J = 7.1 Hz, 1 H), 4.55 (dd, J = 7.8, 12.2 Hz, 1 H), 4.65 (dd, J = 6.8, 12.2 Hz, 1 H), 5.02 (s, 1 H), 6.91-6.95 (m, 2 H), 7.12-7.15 (m, 2 H), 7.31-7.44 (m, 5 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 30.3, 38.3, 46.2, 70.0, 79.6, 115.2, 127.4, 128.0, 128.4, 128.5, 130.9, 136.7, 158.3, 205.5. The ee of the product was determined by HPLC using a Daicel Chiralpak IA column (n-hexane-i-PrOH = 97:3, flow rate 1 mL/min, λ = 230 nm): t _R(major) = 44.5 min; t _R(minor) = 41.1 min. HRMS: m/z calcd for C₁₈H₁₉NNaO₄: 336.1206; found: 336.1215 [M⁺ + Na].
Compound 8l: Following the general procedure, compound 8l was obtained after 2 d at r.t. as a yellow oil in 67% yield. ^¹H NMR (300 MHz, CDCl₃): δ = 2.13 (s, 3 H), 2.88 (d, J = 6.9 Hz, 2 H), 3.97 (q, J = 6.9 Hz, 1 H), 4.56 (dd, J = 8.1, 12.6 Hz, 1 H), 4.67 (dd, J = 6.3, 12.6 Hz, 1 H), 7.07 (dd, J = 2.1, 8.4 Hz, 1 H), 7.32 (d, J = 2.1 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 30.2, 38.0, 45.7, 78.8, 126.9, 129.4, 130.9, 132.0, 133.0, 139.1, 204.6. The ee of the product was determined by HPLC using a Daicel Chiralpak IA column (n-hexane-i-PrOH = 97:3, flow rate 1 mL/min, λ = 230 nm): t _R(major) = 29.1 min; t _R(minor) = 26.1 min. HRMS: m/z calcd for C₁₁H₁₁Cl₂NNaO₃: 298.0008; found: 298.0007 [M⁺ + Na]. [α]_D ^²² -1.53 (c 1.0, CHCl₃, 44% ee).

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24 All calculations were carried out with the Gaussian 09 suite of programs: Frisch MJ. Trucks GW. Schlegel HB. Scuseria GE. Robb MA. Cheeseman JR. Scalmani G. Barone V. Mennucci B. Petersson GA. Nakatsuji H. Caricato M. Li X. Hratchian HP. Izmaylov AF. Bloino J. Zheng G. Sonnenberg JL. Hada M. Ehara M. Toyota K. Fukuda R. Hasegawa J. Ishida M. Nakajima T. Honda Y. Kitao O. Nakai H. Vreven T. Montgomery JA. Peralta JE. Ogliaro F. Bearpark M. Heyd JJ. Brothers E. Kudin KN. Staroverov VN. Kobayashi R. Normand J. Raghavachari K. Rendell A. Burant JC. Iyengar SS. Tomasi J. Cossi M. Rega N. Millam NJ. Klene M. Knox JE. Cross JB. Bakken V. Adamo C. Jaramillo J. Gomperts R. Stratmann RE. Yazyev O. Austin AJ. Cammi R. Pomelli C. Ochterski JW. Martin RL. Morokuma K. Zakrzewski VG. Voth GA. Salvador P. Dannenberg JJ. Dapprich S. Daniels AD. Farkas . Foresman JB. Ortiz JV. Cioslowski J. Fox DJ. Gaussian 09, Revision A.1   Gaussian, Inc.; Wallingford CT: 2009. 

Calculations were carried out by fully optimizing transition structures at the B3LYP/6-31+G(d,p) level and then performing single-point calculations at M062X/6-311+G(d,p) level with correction for solvent using Tomasi’s polarizable continuum model (PCM) for DMSO level. The use of M062X functional was chosen following recent studies carried out by Houk and Papai. See:

26a Rokob TA. Hamza A. Papai I. Org. Lett.  2007,  9:  4279 

26b Wheeler SE. Moran A. Pieniazek SZ. Houk KN. J. Phys. Chem.  2009,  113:  10376 

26

See ref. 25b. Whereas the mean error is estimated of about 2.0 kcal/mol for M062X functional, for B3LYP deviations up to more than 10 kcal/mol could be observed. For this reason, although B3LYP correctly predict the observed enantioselectivity for 4, it cannot be considered representative.